Immunity refers to a self-defense system of a living body against all exogenous high molecular substances (antigens) which invade or enter the living body. Lymphocytes, as a critical component of an immune system, are white blood cells which originate from the bone marrow and circulate in blood and migrate to lymphoid tissues or organs, particularly, lymph nodes, the spleen and the tonsils. As cells involved in immune reactions, B cells, when stimulated by a suitable antigen, rapidly proliferate to form clones from which specific antibodies (immunoglobulin) for neutralizing the antigen are produced. Circulating in the body fluid, the antibodies produced by B cells function to perform humoral immunity. Further, T cells are produced in the thymus and migrate to lymphoid tissues, and are responsible for cell-mediated immunity directly attacking antigens.
One of the most important characteristics of a normal individual is an ability to recognize, respond to, and eliminate non-self-antigens, while not responding harmfully to self-antigens. This non-responding of a living organism to self-antigens is called “immunologic unresponsiveness” or “tolerance”.
When this ability to induce or maintain self-tolerance is troubled, an immune reaction occurs even to the self-antigens, leading to a phenomenon of attacking self-tissues, and autoimmune disease such as multiple sclerosis, diabetes mellitus type 1, rheumatoid arthritis, Hashimoto's thyroiditis is developed in this process. Also, an immune rejection response occurs after a surgical procedure such as transplant.
Meanwhile, an immune rejection response of a recipient to the transplanted cells or organs has to be dealt with, in order to ensure successful organ transplant. T cells are the major mediator of transplant rejection. That is, an immune reaction is induced, leading to transplant rejection, as the T cell receptor perceives the major histocompatibility complex (MHC) expressed on the graft.
Due to recent development of surgical procedure and HLA typing and development of immunosuppressive agents, a success rate of transplant has increased. However, a death rate is still high due to an immune rejection response and immunosuppressive agents. Therefore, there has been a demand for development of novel, effective and safe immunosuppressive agents.
The common object of all the conventional immunosuppressive agents is to suppress T cell-mediated immunity to a graft. Clinically, in order to suppress T cell-mediated acute rejection after clinical transplant, a nonspecific immunosuppressive agent is administered every day (Pirsch, J. D., curr. opin. organ. transplant., 2, 76 to 81, 1997). Examples of immunosuppressive agents generally used include azathioprine and mycophenolate mofetil that contain glucocorticosteroids to inhibit DNA synthesis and thus to suppress T cell proliferation, and cyclosporine A and tacrolimus as calcineurin inhibitors. These drugs have been improved a lot in overcoming an immune rejection response of an organ transplant patient, but they have problems including a temporary therapeutic effect and high toxicity.
Therefore, although it is important to develop an immunosuppressive agent for suppressing transplant rejection, at this point in time when an immunosuppressive agent having a clear therapeutic effect needs to be further developed, the most effective and fastest method for minimizing side effects caused by administration of an immunosuppressive agent is to reduce a dosage of the immunosuppressive agent. However, if a reduced dosage of the immunosuppressive agent is administered to an organ transplant patient due to fear of any side effect without any criteria, there may be an increase in pain due to transplant rejection. Thus, if a method of reducing a dosage of an immunosuppressive agent with respect to a patient in a good immune status and treating a patient, who is not in a good immune status, with an immunosuppressive agent in the same amount as used previously by checking an immune status in an organ transplant patient with general standards is developed, it is possible to reduce pain of the patient caused by the immunosuppressive agent.
As such, immunosuppressive agents, which have been used for a transplant and administered to many patients with immune diseases can cause various side effects in the body, and particularly, as for a patient after surgery such as transplant, there is no alternative but to prescribe an immunosuppressive agents to suppress an immune rejection response even after considering that side effects inevitably occur.
However, since an immunosuppressive agent without any side effect cannot be developed so far, the best method for reducing side effects caused by immunosuppressive agents is to reduce a dosage at this point in time. However, any guideline on timing for reducing a dosage of a drug and the extent of the reduction has not been provided yet.